Aims Itraconazole is a potent inhibitor of CYP3A4 activity and is often used in combination with corticosteroids. Since the latter are partly metabolized by CYP3A4, we studied the interaction between itraconazole, prednisone and methylprednisolone in healthy male subjects. Methods The effects of 4 days administration of oral itraconazole (400 mg on the ®rst day then 200 mg day x1 for 3 days) on the pharmacokinetics of prednisolone after a single oral dose of prednisone (60 mg) and the pharmacokinetics of methylprednisolone after single oral dose of methylprednisolone (48 mg) were studied in 14 healthy male subjects in a two-period cross-over trial. Plasma cortisol concentrations were determined as a pharmacodynamic index. Results Itraconazole increased the mean area under the methylprednisolone concentration-time curve from 2773 ng ml x1 h to 7011 ng ml x1 h (P<0.001) and the elimination half-life from 3.2 h to 5.5 h (P<0.001). The pharmacokinetics of prednisolone were unchanged. Cortisol concentrations at 24 h were lower after administration of methylprednisolone with itraconazole than after methylprednisolone alone (24 ng ml x1 vs 109 ng ml x1 , P<0.001). Conclusions Itraconazole increased methylprednisolone concentrations markedly with enhanced suppression of endogenous cortisol secretion, but had no effect on prednisolone pharmacokinetics. The pharmacokinetic interaction between methylprednisolone and itraconazole is probably related to inhibition of hepatic CYP3A4 activity by itraconazole.
This study evaluated the effects of acute doses of zopiclone (7.5 mg), triazolam (0.25 mg) and placebo on memory and psychomotor performance of 12 normal volunteers. The subjects received both drugs in a repeated measure, double-blind Latin square design. The tests (CFF, CRT, DSST, memory assessments) were performed before and 2 and 6 hr after treatment. Zopiclone and triazolam induced an anterograde amnesia affecting short-term and long-term memory which lasted less than 6 hr. No retrograde amnesia was observed. Two hr after drug intake of both hypnotics psychomotor performances were significantly altered compared with placebo. The subjects also felt more drowsy, dizzy, clumsy and tired, and less alert and energetic 2 hr after zopiclone and triazolam compared to placebo. There was no difference between the effects of the two hypnotics at the doses studied.
To determine the pharmacokinetic, subjective effects of a single 20 mg dose of nefopam administered either intravenously or orally in healthy volunteers, twenty-four healthy Caucasian men received 20 mg nefopam orallyπplacebo intravenous infusion and placebo orallyπintravenous infusion of 20 mg nefopam with one week interval, in a doubleblind, double-dummy cross-over study. Nefopam and desmethyl-nefopam plasma concentrations were measured by HPLC with UV detection up to 48 hr after drug administration. Self-rating questionnaires (Mood and vigilance Visual Analogue Scales, Addiction Research Centre Inventory) and drug safety were investigated. The F value (bioavailability) of the parent drug was 0.36∫0.13. The AUC oral /AUC iv ratio of nefopamπdesmethyl-nefopam was 0.62∫0.23. The half-life of nefopam was similar whether administered orally (5.1∫1.3 hr) or intravenously (5.1∫0.6 hr). The half-life of desmethyl-nefopam was two to three times longer than that of the parent molecule (orally: 10.6∫3.0 versus 5.1∫1.3 hr, PϽ10ª4 and intravenously: 15.0∫2.4 versus 5.1∫0.6 hr, PϽ10 ª4 ). As assessed by the Addiction Research Centre Inventory, no evidence of abuse liability in healthy, drug-naive volunteers was observed. On visual analogue scales, volunteers rated themselves as more drowsy, less alert, less energetic and less anxious after oral compared to intravenous administration. The AUC 0»24 hr of anxiety and energy parameters were not different after oral and intravenous administration: 90∫142 versus 35∫84 (PΩ0.27) and 66∫74 versus 46∫54 mm.hr (PΩ0.36), respectively. The AUC 0»24 hr of drowsiness and alertness parameters were significantly greater after oral than after intravenous administration: 68∫65 versus 27∫30 (PΩ0.005) and 54∫63 versus 28∫48 mm.hr (PΩ0.03), respectively. A clockwise hysteresis loop was observed for drowsiness in 16 out of 24 volunteers after oral administration. The results suggest that in healthy volunteers desmethyl-nefopam may contribute to the pharmacodynamic effects of single dose nefopam solution administered orally. This study shows a rather low bioavailability of nefopam given in intravenous solution when administered orally. Nevertheless, when the main metabolite desmethyl-nefopam is taken into account, the ratio of the areas under the curves is almost doubled.Nefopam is a non-opioid analgesic drug usually administered by intravenous infusion or intramuscular injection for postoperative pain (Calmi et al. 1985;Pandit et al. 1989; Goucke et al. 1990;Guirimand et al. 1990;Moffat et al. 1990). Previous studies in man have shown that 20 mg nefopam reduces daily morphine consumption by 30 % after upper abdominal surgery (McLintock et al. 1988) and by 50% after elective hepatic resection (Mimoz et al. 2001). Results obtained in man on the nociceptive R III reflex suggest that nefopam probably exerts its analgesic action through central (spinal and/or supraspinal) mechanisms. An oral formulation of nefopam is not available in France. Oral administration of intravenous solution of n...
E even at low doses and by the nasal route can decrease tiredness in healthy persons; this is accompanied by a substantial increase in blood pressure and orthostatic hypotension exposing individuals in case of intensive physical exercise to cardiovascular risks. No clear evidence of abuse liability in healthy drug naive subjects was observed.
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